Tylenol

"Nov. 26, 2014 -- Gift-buying season is here, and on top of the wish list for most people is the latest tech gadget or gizmo. But some experts are concerned that more tech may equal more pain for frequent users.

Tylenol

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Safety Perspectives, Toxicology, And Special Precautions

a. Safety

Central Nervous System Effects

Acetaminophen at recommended doses has no obvious effects on central nervous
system function.33 In an overdose situation, central nervous system
effects are uncommon. Coma or other evidence of central nervous system depression
usually is not present unless the patient has taken a massive overdose, has
taken other central nervous system-active agents concomitantly, or is experiencing
central nervous system effects secondary to fulminant hepatic failure.

Cross-Reactivity of Acetaminophen With Aspirin and NSAIDs

Most studies do not show any cross-reactivity with the use of acetaminophen
in aspirin-sensitive patients.82-85 In one study, when asthmatic
patients who were sensitive to very low doses of aspirin were challenged with
doses of 1000 to 1500 mg of acetaminophen, a proportion had evidence of decreased
pulmonary forced expiratory volume at 1 second (FEV1), but, in contrast
to the aspirin reactions, the reactions to acetaminophen were generally mild
and easily reversed.86 No reactions were seen with acetaminophen
at doses of 650 mg or less. Acetaminophen is recommended as the analgesic/antipyretic
of choice in aspirin/NSAID-sensitive patients.

Gastrointestinal Effects

In recommended therapeutic doses, acetaminophen does not cause gastric irritation,
gastric erosions, occult or overt gastrointestinal blood loss, or ulcers.87,88
In a placebo-controlled, randomized, double-blind, crossover, endoscopy study
in 12 healthy volunteers, 1000 mg of aspirin evoked a lesion score of 2.5 (possible
scores ranged from 0 [no mucosal lesions] to 3 [more than 10 petechiae or free
blood in the lumen]), whereas 1000 mg of acetaminophen and placebo resulted
in scores of 1.0 and 0.92, respectively.89 Several case-controlled
studies have established that gastrointestinal bleeding is a significant risk
with both regular and occasional aspirin or NSAID use, whereas acetaminophen
is not associated with a risk for gastrointestinal bleeding.90-92
a case-controlled study evaluating first-time peptic ulcer patients found no
significant risk associated with acetaminophen use prior to gastric ulcer occurrence,
whereas this was not the case with aspirin.93 An American College
of Gastroenterology survey found that OTC aspirin and NSAIDs were used significantly
more often by patients in the gastrointestinal bleeding population than in controls.
However, this was not the case with acetaminophen.94

Hematologic Effects

A case-controlled, multicenter study established that acetaminophen is not
associated with agranulocytosis or aplastic anemia.95 Although there
have been infrequent reports, primarily letters to the editor, in which thrombocytopenia
was noted in patients receiving acetaminophen, no causality was established.96-101

Hemostatic Effects

In various clinical conditions, acetaminophen may be preferred because it does
not have any immediate or delayed effects on small-vessel hemostasis, as measured
by bleeding time. In normal volunteers receiving a single dose of acetaminophen
(975 or 1950 mg) or multiple doses of acetaminophen (1950 mg daily for 6 weeks),
no change in bleeding time or platelet aggregation was observed.102
In another study, a single 1000-mg dose of acetaminophen was given to normal
volunteers and did not affect bleeding time or platelet aggregation. 103
Patients with hemophilia receiving multiple doses of acetaminophen showed no
significant changes in bleeding time.104,105

Hepatic Effects

In clinical studies in adults, acetaminophen when taken in therapeutic doses
of up to 4000 mg/d demonstrated no adverse hepatic effects. Two double-blind,
randomized, controlled trials have demonstrated the safety of acetaminophen
with chronic use. In one study, Bradley and colleagues49 compared
acetaminophen (4000 mg/d) with analgesic (1200 mg/d) and anti-inflammatory (2400
mg/d) doses of ibuprofen for 4 weeks. In the second study, Williams and associates50
evaluated the relative safety and efficacy of acetaminophen (2600 mg/d) compared
with naproxen (750 mg/d) for up to 2 years. In both of these studies, no clinically
important hepatic events occurred in aceta-minophen-treated patients. In a large
clinical study, Lesko and Mitchell106 enrolled more than 84,000 febrile
children in a randomized, double-blind, acetaminophen-controlled trial to assess
the risks of rare but serious adverse events following use of pediatric ibuprofen.
Of the children included in the analysis, 28,130 received acetaminophen
and none experienced serious adverse hepatic effects.

Acetaminophen in massive overdosage may cause hepatotoxicity in some patients.
In adults and adolescents, hepatotoxicity may occur following ingestion of greater
than 7.5 to 10 g (ie, 24 regular-strength or 15 extra-strength caplets or tablets)
over a period of 8 hours or less. Fatalities are infrequent (less than 3% to
4% of untreated cases) and have rarely been reported with overdoses less than
15 g (ie, 45 regular-strength or 30 extra-strength caplets or tablets). In children,
amounts less than 150 mg/kg are highly unlikely to produce hepatotoxicity. In
both adults and children, toxicity associated with acetaminophen is almost invariably
caused by ingestion of quantities of the drug that are significantly above the
recommended dosage range. Hepatotoxicity, ranging from transient sharp transaminase
elevations to fatal, fulminant hepatic failure, is the most common result of
clinically significant overdosage.107

Chronic heavy alcohol abusers may be at increased risk of liver toxicity from
excessive acetaminophen use, although reports of this event are rare. Although
some authors suggest that alcoholics may be at increased risk from therapeutic
doses, reports usually involve cases of severe chronic alcoholics and the dosages
of acetaminophen most often exceed recommended doses and often involve substantial
overdose.108-110 Studies evaluating the metabolism of doses up to
20 mg/kg of acetaminophen in chronic alcohol abusers and a study evaluating
the effects of 2 days of acetaminophen dosing at 4000 mg daily in chronic alcoholics
undergoing detoxification do not support an increased risk of hepatotoxicity
with recommended doses of acetaminophen.111-115

A report has suggested that hepatotoxicity following greater than the recommended
dose of acetaminophen may be enhanced by both fasting and/or chronic alcohol
ingestion.116 Review of this case series revealed that all patients
reported taking overdoses of acetaminophen, most had reported prolonged periods
of fasting, and the majority had a history of the abuse of alcohol.

Hypersensitivity and Allergy

Allergic reactions (primarily skin rash) or reports of hypersensitivity secondary to acetaminophen are rare and generally are controlled by discontinuation of the drug and, when necessary, symptomatic treatment.

Pregnancy/Teratogenicity

Acetaminophen labeling, like all OTC medications, instructs consumers who are pregnant or nursing a baby to contact their doctor before use. Acetaminophen has been used for over 40 years and available data indicate that acetaminophen in therapeutic doses does not adversely affect the pregnant mother or the fetus.

Transplacental Passage

Analysis of urine samples has demonstrated the passage of unconjugated acetaminophen
via placental transfer.23 When given to the mother in therapeutic
doses, acetaminophen crosses the placenta into fetal circulation as early as
30 minutes after ingestion, although the difference in serum concentration between
maternal and cord blood is not statistically significant.24 In the
fetus, acetaminophen is effectively metabolized by sulfate conjugation.25

Nursing

Maternal ingestion of acetaminophen in recommended analgesic doses does not
present a risk to the nursing infant. Amounts in milk range from 0.1% to 1.85%
of the ingested maternal dose.26-28 These studies have established
that, even at the time of peak acetaminophen concentration in human breast milk,
the nursing infant would receive less than 2% of the maternal dose. Accordingly,
breast feeding need not be interrupted because of maternal medication with recommended
doses of acetaminophen.

Overdose

One study that evaluated the subsequent outcome of pregnancy in women who had
taken an acetaminophen overdose during the period from 1984 to 1992 demonstrated
no increased risk for fetal malformation. Acetaminophen overdose alone is not
an indication for termination of pregnancy.117

Renal Effects

Clinical data have established that acetaminophen in recommended doses is not
nephrotoxic.33 In a single-blind study, Prescott and colleagues118
compared the effect of acetaminophen (4000 mg/d) with indomethacin (150 mg/d)
and placebo on renal function in healthy volunteers. Acetaminophen did not have
the adverse renal effects generally associated with NSAIDs. Edwards and associates119
measured renal function in patients taking at least 1000 mg of acetaminophen
daily for at least 1 year. There was no evidence of clinically significant renal
impairment in 18 patients who each consumed a cumulative total of 2 to 30 kg
of acetaminophen over prolonged periods.

Acute nephrotoxicity has been reported following massive overdose either as
a sequela of hepatic failure or, occasionally, in the absence of hepatic failure.120

Some studies suggest an association between the chronic long-term use of acetaminophen
and renal effects. Results, however, are conflicting, limited by recall bias
and confounded by the inability to determine whether analgesic use preceded
or followed the onset of renal disease.119,121-125

A National Kidney Foundation position paper notes that there is negligible
clinical evidence to suggest that the habitual use of acetaminophen causes analgesic
nephropathy.126 However, use of antipyretic analgesic combinations (ie, analgesics
that contain aspirin and acetaminophen combined with caffeine or codeine) in
large doses for prolonged periods of time is thought to be associated with an
increased risk of renal papillary necrosis resulting in analgesic nephropathy.126
The panel concludes that acetaminophen has been preferentially recommended by
physicians to patients with renal failure and that there is no evidence that
occasional use of acetaminophen causes renal injury. In this position paper,
acetaminophen was recommended as the non-narcotic analgesic of choice for episodic
use in patients with underlying renal disease.

b. Use in Certain Disease States or Conditions

In therapeutic doses, acetaminophen does not shorten the lifespan of red blood
cells127,128 and does not produce any clinically perceptible destruction
of circulating red blood cells.129

Use in Chronic Liver Disease

Acetaminophen can be used in patients with liver disease130 and
has been studied in both one-time single (1500 mg) and multiple doses (4000
mg/d) in adult patients with chronic stable liver disease.131,132
Benson131 conducted a double-blind, two-period, crossover study that
evaluated the use of 4000 mg/d of acetaminophen for 13 days in patients with
stable chronic liver disease. There were no abnormalities indicative of an adverse
reaction to acetaminophen. Forrest and associates132 compared acetaminophen
metabolism following a single 1500-mg dose in normal subjects, patients with
mild liver disease, and patients with severe liver disease. There were no significant
differences in overall 24-hour urinary excretion of acetaminophen and glucuronide,
sulfate, cysteine, and mercapturic acid conjugates of acetaminophen. Following
a single (10 mg/kg) dose of acetaminophen, the pharmacokinetic profiles in pediatric
patients with mild, moderate, or severe liver disease were not significantly
different.133 Although the plasma half-life of acetaminophen was prolonged in
patients with severe liver disease, there were no significant differences in
the 24-hour (adult) and 36-hour (children) urinary excretion of acetaminophen
or its conjugates (eg, glucuronide, sulfate, cysteine, mercapturic acid).

Use in Renal Disease

Based on available clinical data, acetaminophen can be used in patients with
chronic renal disease without dosage adjustment. In a single-dose study, Prescott
and colleagues134 compared the disposition and metabolite kinetics
of 1000 mg of acetaminophen in patients with renal disease and in healthy volunteers.
The fractional urinary recovery of acetaminophen and its conjugates (eg, glucuronide,
sulfate, cysteine, mercapturate) was similar in healthy volunteers and in patients
with moderate renal failure. In a 10-day, multi-dose study, Martin and associates135
evaluated the disposition of acetaminophen 3000 mg daily in healthy volunteers
compared with patients with chronic renal failure. A slight increase in predose
trough acetaminophen levels was noted in patients with renal failure (3.1 µg/mL)
compared with controls (1.1 µg/mL), but there was no evidence of accumulation
of the glutathione-derived metabolites of acetaminophen (eg, cysteine, mercapturate).
Although mean daily predose plasma concentrations of sulfate and glucuronide
conjugates were higher in patients with chronic renal disease, these conjugates
disappeared rapidly when acetaminophen was discontinued. There is no significant
risk of acetaminophen toxicity in patients with moderate to severe renal failure.

A National Kidney Foundation position paper notes that physicians preferentially
recommend acetaminophen to patients with renal failure because of the bleeding
complications associated with aspirin in these individuals.126 In
this position paper, acetaminophen was recommended as the non-narcotic analgesic
of choice for episodic use in patients with underlying renal disease.

Use in Older Patients

No adjustment in labeled dosage is necessary for older patients who require
acetaminophen therapy. Those who require therapy for longer than 10 days should
consult their physician for condition monitoring; however, no reduction in recommended
dosage is necessary. The American Geriatrics Society Clinical Practice Guidelines
for the Management of Chronic Pain in Older Persons136 recommend
acetaminophen as the drug of choice for relieving mild to moderate musculoskeletal
pain, with the maximum dosage not to exceed 4000 mg daily.

Carcinogenicity/Mutagenicity (Animal)

Various animal bioassays on a weight-of-evidence basis have demonstrated no
evidence of carcinogenic potential for acetaminophen. The International Agency
for Research on Cancer (IARC) found only limited evidence in animals for carcinogenicity
and the US National Toxicology Program (NTP) found no evidence for carcinogenicity
in mice and male rats and only equivocal evidence for carcinogenicity in female
rats.161,162 The equivocal results were based on a few studies with
serious methodological problems. Negative results have been demonstrated in
rodent bioassays of acetaminophen.163

Carcinogenicity (Human)

Although it has been hypothesized that long-term use of analgesics may be associated
with a slight increase in urinary tract tumors and renal cell cancer in man,
a number of population-based, case-controlled studies have shown that it is
not likely that acetaminophen use plays a major role in renal cell cancer.164-166

A comprehensive and conclusive review, accepted by the Committee for Proprietary
Medicinal Products (CPMP) of the European Union, considered the genotoxic and
carcinogenic properties of acetaminophen.167 This review concluded
that genotoxic effects of acetaminophen are not reached at therapeutic dosage.

Reproductive and Teratogenic Effects (Animal)

There was no effect on pregnancy or offspring when acetaminophen was given
at dose levels of 600 mg/kg/d in the diet of male rats for 60 days prior to
mating and to female rats from 14 days before mating to the end of pregnancy.
An oral dose of 600 mg/kg/d produced no teratogenicity or embryotoxicity when
given from days 6 through 15 of pregnancy. When acetaminophen was given from
day 16 of pregnancy through a 3-week lactation period, no deleterious effect
was noted on pregnancy rate or on percent of live births, but a decrease in
body weight gain and survival rate was noted among offspring of drug-treated
females.168,169 In another study, acetaminophen 250 mg/kg/d did not
affect fetal length or weight, incidence of resorptions, or placental weight.170

Potential Laboratory Test Interferences

Using the most current analytic systems, acetaminophen does not cause laboratory
test interferences. However, there are certain methods with which the possibility
of laboratory changes exists, as described below:

Blood Tests

Acetaminophen at recommended doses does not appear to interfere with glucose
analysis using currently marketed blood glucose meters. For further detail,
it may be advisable to contact the specific laboratory instrumentation manufacturer.

Urine Tests

Acetaminophen in therapeutic doses may interfere with the determination of
5-hydroxyindoleacetic acid (5HIAA), causing false-positive results. False determinations
may be eliminated by avoiding acetaminophen ingestion several hours before and
during the collection of the urine specimen.155

94. Peura DA, Lanza FL, Gostout CJ, Foutch PG, and contributing
ACG member and fellows. Report of the American College of Gastroenterology Institute
for Clinical Research and Education: The American College of Gastroenterology
Bleeding Registry: Preliminary Findings. Am J Gastroenterol. 1997;92:924-928.